rs11855415

Variant names:

• chr15-101334918-A-T
• rs11855415
• NM_002570.5:c.1859-2887T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002570.5(PCSK6):​c.1859-2887T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 152,016 control chromosomes in the GnomAD database, including 48,369 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.80 (48369 hom., cov: 30)
• Consequence: PCSK6 NM_002570.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0930
• Publications: 24 publications found

Genes affected

PCSK6 (HGNC:8569): (proprotein convertase subtilisin/kexin type 6) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. The encoded protease is constitutively secreted into the extracellular matrix and expressed in many tissues, including neuroendocrine, liver, gut, and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. Some of its substrates include transforming growth factor beta related proteins, proalbumin, and von Willebrand factor. This gene is thought to play a role in tumor progression and left-right patterning. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Feb 2014]

PCSK6-AS1 (HGNC:51448): (PCSK6 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK6	NM_002570.5	c.1859-2887T>A		intron_variant	Intron 13 of 21	ENST00000611716.5	NP_002561.1
PCSK6	NM_138319.4	c.1859-2887T>A		intron_variant	Intron 13 of 20		NP_612192.1
PCSK6	NM_001291309.2	c.1637-2887T>A		intron_variant	Intron 11 of 19		NP_001278238.1
PCSK6-AS1	NR_132373.1	n.77+405A>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK6	ENST00000611716.5	c.1859-2887T>A		intron_variant	Intron 13 of 21	1	NM_002570.5	ENSP00000482760.1

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120911 AN: 151898 Hom.: 48328 Cov.: 30

Gnomad AFR AF: 0.851

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.831

Gnomad ASJ AF: 0.689

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.761

Gnomad NFE AF: 0.779

Gnomad OTH AF: 0.790

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.796 AC: 121008 AN: 152016 Hom.: 48369 Cov.: 30 AF XY: 0.791 AC XY: 58770 AN XY: 74270

African (AFR) AF: 0.851 AC: 35293 AN: 41466

American (AMR) AF: 0.831 AC: 12713 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 2388 AN: 3466

East Asian (EAS) AF: 0.789 AC: 4071 AN: 5162

South Asian (SAS) AF: 0.587 AC: 2818 AN: 4804

European-Finnish (FIN) AF: 0.770 AC: 8104 AN: 10530

Middle Eastern (MID) AF: 0.771 AC: 225 AN: 292

European-Non Finnish (NFE) AF: 0.779 AC: 52965 AN: 67982

Other (OTH) AF: 0.788 AC: 1663 AN: 2110

Alfa AF: 0.785 Hom.: 5837

Bravo AF: 0.812

Asia WGS AF: 0.702 AC: 2441 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	6.3
DANN	Benign	0.73
PhyloP100		0.093
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11855415; hg19: chr15-101875123;